This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The central goal of this project is to assess the mechanisms of adipose tissue insulin resistance. In this R01, we will examine ex vivo adipose tissue metabolism among non-obese individuals of all ethnicities. Whole-body metabolic assessments including euglycemic - hyperinsulinemic clamps are central to this project. As a consequence of this work and observations in other labs, it is becoming increasingly evident that there are significant ethnic differences in susceptibility to metabolic complications of obesity, particularly type 2 diabetes. For example, we have shown that Asian Indians have significantly higher insulin resistance compared to Caucasians for similar BMI, body fat and lower waist circumference, even below the cutoffs suggested by the International diabetes foundation. We have established that Asian Indians with increased insulin resistance compared to Caucasians do not have increased abdominal fat contrary to popular misconception among investigators. More recently, we have found that the plasma concentration of adipose tissue metabolites leptin and non-esterified fatty acids (NEFAs) were higher and that of adiponectin were lower in insulin resistant healthy Asian Indians compared to more insulin sensitive Caucasians. Again, these differences in biomarkers of adipose tissue metabolism are not explained by degree of adiposity or by fat distribution. Taken together, these studies support the notion that adipose tissue metabolism is dysfunctional in Asian Indians susceptible to insulin resistance evening the absence of obesity. However, the role of hepatic glucose production and hepatic contribution to increased plasma free fatty acid in ethnic differences in NEFA is still not understood. We therefore propose to extend our lab's current work on ENPP1 and adipose tissue, and to compare hepatic b oxidation and hepatic glucose production by stable isotope technique in healthy young Asian Indians and Caucasians matched for total body fat. The overall hypothesis of the project is that ethnic minorities will have defective hepatic beta oxidation which will explain increased plasma NEFA and insulin resistance independent of obesity. The long term goal of our proposal is to determine the mechanisms whereby hepatic beta oxidation and adipose tissue dysfunction account for susceptibility to insulin resistance in all US ethnic minorities. However, this proposal will focus on comparing South Asians with Caucasians for a variety of reasons, including the rapidly growing number of South Asians in the US, the presence of established susceptibility to insulin resistance in South Asians, the need for extensive metabolic studies and the limited duration of this grant mechanism and our track record of effectively recruiting these subjects. The specific aim and hypothesis to be tested are: To compare hepatic glucose production and hepatic beta oxidation in non-diabetic volunteers of Caucasian and South Asian descent. The hypothesis for this specific aim is that South Asians will have increased hepatic glucose production and decreased beta oxidation compared to Caucasians, independent of total and abdominal fat content. The result form this study will establish if defective hepatic beta oxidation plays a role in ethnic susceptibility to higher NEFA and insulin resistance, especially in South Asians. If confirmed, the data from this study will set the bases for further evaluation of the genetic/ environmental factors that are mechanistically responsible for adipose tissue dysfunction, and for identifying biomarkers and possible targets of intervention for more effective prevention of type 2 diabetes and related cardiovascular complications in all US ethnic groups. To accomplish this aim we will study 20 South Asian and 20 Caucasians as pilot study who are non-obese and non diabetic. We will study them in fasting condition.